Journal article
Authors list: Williamson, Kathleen A.; Hall, H. Nikki; Owen, Liusaidh J.; Livesey, Benjamin J.; Hanson, Isabel M.; Adams, G. G. W.; Bodek, Simon; Calvas, Patrick; Castle, Bruce; Clarke, Michael; Deng, Alexander T.; Edery, Patrick; Fisher, Richard; Gillessen-Kaesbach, Gabriele; Heon, Elise; Hurst, Jane; Josifova, Dragana; Lorenz, Birgit; McKee, Shane; Meire, Francoise; Moore, Anthony T.; Parker, Michael; Reiff, Charlotte M.; Self, Jay; Tobias, Edward S.; Verheij, Joke B. G. M.; Willems, Marjolaine; Williams, Denise; van Heyningen, Veronica; Marsh, Joseph A.; FitzPatrick, David R.
Publication year: 2020
Pages: 598-609
Journal: Genetics in Medicine
Volume number: 22
Issue number: 3
ISSN: 1098-3600
eISSN: 1530-0366
Open access status: Hybrid
DOI Link: https://doi.org/10.1038/s41436-019-0685-9
Publisher: Elsevier
Abstract:
Purpose Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. Methods We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGU(eye)) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. Results Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. Conclusion Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.
Citation Styles
Harvard Citation style: Williamson, K., Hall, H., Owen, L., Livesey, B., Hanson, I., Adams, G., et al. (2020) Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction, Genetics in Medicine, 22(3), pp. 598-609. https://doi.org/10.1038/s41436-019-0685-9
APA Citation style: Williamson, K., Hall, H., Owen, L., Livesey, B., Hanson, I., Adams, G., Bodek, S., Calvas, P., Castle, B., Clarke, M., Deng, A., Edery, P., Fisher, R., Gillessen-Kaesbach, G., Heon, E., Hurst, J., Josifova, D., Lorenz, B., McKee, S., ...FitzPatrick, D. (2020). Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction. Genetics in Medicine. 22(3), 598-609. https://doi.org/10.1038/s41436-019-0685-9
Keywords
ANIRIDIA; ANOPHTHALMIA; HOMEODOMAIN; MALFORMATIONS; MICROPHTHALMIA; missense variant; paired domain; protein destabilization; SOX2
